The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas

Author(s)

Seguin, F. ^[1] ; Carvalho, M. A. ^[1] ; Bastos, D. C. ^[1] ; Agostini, M. ^[1] ; Zecchin, K. G. ^[1] ; Alvarez-Flores, M. P. ^[2] ; Chudzinski-Tavassi, A. M. ^[2] ; Coletta, R. D. ^[1] ; Graner, E. ^[1]

Affiliation

^[1] Univ Campinas UNICAMP, Sch Dent Piracicaba, Dept Oral Diag, BR-13414018 Piracicaba, SP - Brazil

^[2] Butantan Inst, Biochem & Biophys Lab, BR-05503900 Sao Paulo - Brazil

• Document type: Journal article
• Source: BRITISH JOURNAL OF CANCER; v. 107, n. 6, p. 977-987, SEP 4 2012.
• Web of Science Citations: 63

Abstract

BACKGROUND: Fatty acid synthase (FASN) is overexpressed and associated with poor prognosis in several human cancers. Here, we investigate the effect of FASN inhibitors on the metastatic spread and angiogenesis in experimental melanomas and cultured melanoma cells. METHODS: The lung colonisation assay and cutaneous melanomas were performed by the inoculation of mouse melanoma B16-F10 cells in C57BL6 mice. Blood vessel endothelial cells (RAEC and HUVEC) were applied to determine cell proliferation, apoptosis, and the formation of capillary-like structures. Vascular endothelial growth factor A (VEGFA) expression was evaluated by quantitative RTPCR and ELISA in B16-F10, human melanoma (SK-MEL-25), and human oral squamous carcinoma (SCC-9) cells. Conditioned media from these cancer cell lines were used to study the effects of FASN inhibitors on endothelial cells. RESULTS: B16-F10 melanoma-induced metastases and angiogenesis were significantly reduced in orlistat-treated mice. Fatty acid synthase inhibitors reduced the viability, proliferation, and the formation of capillary-like structures by RAEC cells, as well as the tumour cell-mediated formation of HUVEC capillary-like structures. Cerulenin and orlistat stimulated the production of total VEGFA in B16-F10, SK-MEL-25, and SCC-9 cells. Both drugs also enhanced VEGFA(121, 165, 189), and (165b) in SK-MEL-25 and SCC-9 cells. CONCLUSION: FASN inhibitors reduce metastasis and tumour-induced angiogenesis in experimental melanomas, and differentially modulate VEGFA expression in B16-F10 cells. British Journal of Cancer (2012) 107, 977-987. doi:10.1038/bjc.2012.355 www.bjcancer.com Published online 14 August 2012 (C) 2012 Cancer Research UK (AU)

• FAPESP's process: 08/57471-7 - The role of fatty acid synthase activity in apoptosis, metastasis and vasculogenesis in melanoma
• Grantee: Edgard Graner
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/51090-1 - Evaluation of the biological role of fatty acid synthase (FASN) enzyme in lymphatic endothelial cells stimulated by malignant cells in culture
• Grantee: Débora Campanella Bastos
• Support Opportunities: Scholarships in Brazil - Doctorate